An Etonogestrel/Ethinyl Estradiol/QGriffithsin (EEQ) IVR to Prevent Pregnancy and HIV Several multipurpose prevention technologies (MPTs) have been advanced to prevent unintended pregnancy and HIV. The current MPT development pipeline is dominated by antiretroviral (ARV) products with progestin- only contraception using levonorgestrel. The Population Council, in collaboration with Oak Crest Institute of Science (OCIS), proposes to develop a 90d pod-type IVR containing the progestin etonogestrel (ETG), the estrogen ethinyl estradiol (EE), and the anti-HIV lectin QGriffithsin (QGRFT), hereafter referred to as the EEQ IVR, to prevent unintended pregnancy and HIV. This product offers a highly effective contraceptive combination (used in NuvaRing) with the extremely potent and stable non-ARV anti-HIV lectin QGRFT. The EEQ IVR offers significant advantages over ARV/progestin-only contraceptive products. It could reduce both the emergence of drug-resistant HIV and the concern of potential increased risk of HIV transmission as well as common irregular bleeding complaints associated with use of a progestin-only contraceptive. Aim 1: The proposed product development plan for the EEQ IVR includes innovative formulation work involving pod IVR designs and the use of silk fibroin to achieve QGRFT release for 90d. We will develop a scalable process to manufacture an EEQ IVR. Aim 2: Two lead EEQ IVRs will be tested in safety/pharmacokinetics/pharmacodynamics studies in rhesus macaques (RMs). We intend that the EEQ IVR will be safe, deliver target API doses for 90d in vivo and demonstrate in vitro efficacy against HIV/SHIV AD8. Based on these studies, the lead RM IVR will be selected and advanced to in vivo efficacy studies in RMs. We postulate that the EEQ IVR will be efficacious against SHIV AD8 in vivo and will not drive resistance. Aim 3: We will conduct a pilot study among 24 US couples to compare adherence, preference and acceptability of 3 placebo silicone IVRs of different external diameters (46mm, 56mm and 66mm) to inform the design of the EEQ IVR. Using a 3-way crossover study design, we will identify the external IVR diameter associated with greatest adherence and preference to inform the final EEQ IVR design. The EEQ IVR has the potential to significantly improve women?s health and advance the MPT and drug delivery fields. The EEQ IVR would be the first non-ARV MPT for women at high risk for both unintended pregnancy and HIV acquisition.